Thiophenopyrimidines

Abstract

This invention concerns compounds of formulaincluding the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein X is S, SO or SO2; R1 is NR4R5 or OR5; R2 is C1-6alkyl, C1-6alkyloxy or C1-6alkylthio; R3 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfoxy or C1-6alkylthio; R4 is hydrogen, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl, C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl or C1-6alkyloxyC1-6alkyl; R5 is C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, Ar1CH2, C1-6alkyloxy-C1-6alkyl, hydroxyC1-6alkyl, C3-6alkenyl, thienylmethyl, furanylmethyl, C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)amino, C1-6alkylcarbonylC1-6alkyl, C1-6alkyl substituted with imidazolyl; or a radical of formula -Alk-O-CO-Ar1; or R4 and R5 taken together with the nitrogen atom to which they are attached may form an optionally substituted pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group; Ar is phenyl, substituted phenyl, pyridinyl or substituted pyridinyl; having CRF receptor antagonistic properties; pharmaceutical compositions containing such compounds as active ingredients; methods of treating disorders related to hypersecretion of CRF such as depression, anxiety, substance abuse, by administering an effective amount of a compound of formula (I).

What is claimed is:  
     
       1. A process for preparing a compound of the formula:                    
       including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein 
       X is S, SO or SO 2 ;  
       R 1  is NR 4 R 5  or OR 5 ;  
       R 2  is C 1-6 alkyl, C 1-6 alkyloxy or C 1-6 alkylthio;  
       R 3  is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfoxy or C 1-6 alkylthio;  
       R 4  is hydrogen, C 1-6 alkyl, mono- or di(C 3-6 cycloalkyl)methyl, C 3-6 cycloalkyl, C 3-6 alkenyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyloxyC 1-6 alkyl or C 1-6 alkyloxyC 1-6 alkyl;  
       R 5  is C 1-8 alkyl, mono- or di(C 3-6 cycloalkyl)methyl, Ar 1 CH 2 , C 3-6 alkenyl, C 1-6 alkyloxyC 1-6 alkyl, hydroxyC 1-6 alkyl, thienylmethyl, furanylmethyl, C 1-6 alkylthioC 1-6 alkyl, morpholinyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylC 1-6 alkyl, C 1-6 alkyl substituted with imidazolyl; or a radical of formula -Alk-O-CO-Ar 1 ;  
       or R 4  and R 5  taken together with the nitrogen atom to which they are attached may form a pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group, optionally substituted with C 1-6 alkyl or C 1-6 alkyloxyC 1-6 alkyl;  
       Ar is phenyl; phenyl substituted with 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl, trifluoromethyl, hydroxy, cyano, C 1-6 alkyloxy, benzyloxy, C 1-6 alkylthio, nitro, amino and mono- or di(C 1-6 alkyl)amino; pyridinyl; pyridinyl substituted with 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl, trifluoromethyl, hydroxy, cyano, C 1-6 alkyloxy, benzyloxy, C 1-6 alkylthio, nitro, amino, mono- or di(C 1-6 alkyl)amino and piperidinyl; and wherein said substituted phenyl may optionally be further substituted with one or more halogens;  
       Ar 1  is phenyl; phenyl substituted with 1, 2 or 3 subsitutuents each independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy, di(C 1-6 alkyl)aminoC 1-6 alkyltrifluoromethyl, and C 1-6 alkyl substituted with morpholinyl; or pyridinyl;  
       Alk is C 1-6 alkanediyl; which process comprises:  
       a) alkylating a thiazolopyrimidine of formula (II) with an intermediate of formula (III) under conditions effective to alkylate said thiazolopyrimidine to form a compound of Formula I:                    
       b) O-alkylating a compound of formula (IX) with a compound of formula (X) in the presence of a suitable base under conditions effective to form a compound of formula (I-a), wherein R 1  is OR 5 ,                    
        wherein in the above reaction schemes the radicals R 1 , R 2 , R 3 , R 5  and Ar are as defined and W is a leaving group;  
       and optionally converting the compounds of formula (I), into an acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; and, optionally preparing stereochemically isomeric forms thereof.  
     
     
       2. A process for preparing a compound of formula (II′-a)                    
       or a stereoisomeric form or an acid addition salt thereof wherein W′ is hydroxy, halo, mesyloxy or tosyloxy; 
       R 2  is C 1-6 alkyl, C 1-6 alkyloxy or C 1-6 alkylthio;  
       R 3  is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfoxy or C 1-6 alkylthio; and  
       Ar is phenyl; phenyl substituted with 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl, trifluoromethyl, hydroxy, cyano, C 1-6 alkyloxy, bennyloxy, C 1-6 alkylthio, nitro, amino and mono- or di(C 1-6 alkyl)amino; pyridinyl; pyridinyl substituted with 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl, trifluoromethyl, hydroxy, cyano, C 1-6 alkyloxy, benzyloxy, C 1-6 alkylthio, nitro, amino, mono- or di(C 1-6 alkyl)amino and piperidinyl; and wherein said substituted phenyl may optionally be further substituted with one or more halogens;  
       which process comprises: 
       cyclizing an intermediate of formula (VIII) under effective cyclization conditions to yield an intermediate of formula (II′-b);                    
       and optionally converting compounds of formula (II′-b) into compounds of formula (II′-a), wherein W is halo, mesyloxy or tosyloxy; 
       and optionally converting the compounds of formula (II′-a), into an acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; or optionally preparing stereochemically isomeric forms thereof.